CANCERIMMUNOLOGYRESEARCHPROGRAM PROGRAMCODE:CI PROJECTSUMMARY/ABSTRACT TheoverarchingmissionoftheCancerImmunology(CI)ResearchProgramistoimproveunderstandingofthe hostresponsetocancerandtodiscoverandtestnovelapproachestoharnessthatresponsetoimprove patientoutcomes.Theprogramwasrankedoutstandinginthelastrenewal.Drs.DhodapkarandChenlead theCIprogramandareexperiencedinvestigatorswitha>15-yearhistoryofsustainedNCIfundingand multiplecontributionsincancerimmunology.Dr.ChenpioneeredthetargetingofthePD-1/PD-L1pathwayin cancer,whichhastransformedcancerimmunotherapy.CIconsistsof33membersfrom8different departmentswhoseworkrevolvesaroundfourmajoraims:1)understandthemechanismsunderlyingthe capacityoftheimmunesystemtoinhibittumorgrowth,aswellasmechanismsthatdrivetumorimmune resistance;?2)discoverandtestnewapproachesforpromotinganti-tumorimmunity;?3)studythemechanistic linksbetweeninflammationandcancer;?and4)undertaketargetedtherapeutictrialsthatutilizenovelendpoint assessmentandbuildonthefundamentaldiscoveriesofAims1-3.CIexperienceda15%increaseintotal funding($12Mdirect),aswellasa21%increaseinNCIfunding($2.3Mdirect).Collaborationsremain strongwith17%intra-and30%inter-programmaticpublications. TranslationaleffortsintheCIprogramareabundant,inparticularwithourtumorimmuno-oncology(TIL)lab. MajorcollaborationsexistwiththeLungCancerSPOREandSU2Cefforts(DT),theGU/Bladdergroup(ST), thePhaseIteam(DT),HeadandNeckCancers(DT),andthecolorectalcancerSU2Ccollaborative(CPC). SamplesarebeinganalyzedinnumerousCIclinicaltrialstoinvestigatethemechanismsunderlyingresistance andresponsetoimmunetherapies.Humantissuehasbeencollectedundermultipleprotocolsandusedfor patient-derivedxenograft(PDX)andhumanizedmodels. Duringthelastfundingperiod,immunecheckpointblockadeforcancertreatmenthasemergedasoneofthe mostexcitingandpromisingnewapproachestotreatcancerindecades.CIhasplayedaleadingrolein bringingthisrevolutionaryapproachintotheclinicwithseveralseminalstudiesthatintroducedcheckpoint blockadetargetingthePD1/PD-L1pathwayinthetherapyofmelanoma,lung,gastric,head/neck,andbladder cancer.YCChasbeenattheforefrontoftheimmuno-oncologyrevolution,playingleadrolesintheearliest studiesand,eventually,FDAapprovalsofimmunecheckpointblockadeandcombinationblockade,the identificationofnewcheckpointinhibitortargets,thedevelopmentofuniqueanimalmodels,andimportant advancesinbasicimmunobiology,especiallyinT-cellbiology.Overthelastfiveyears,thegrowthofour clinicaltrialeffortsinthisareahasenabledreversetranslationusingclinicalspecimens,whichbolstersSPORE andothermulti-PIgrants.CIwillcontinueasahighlyinteractiveprogramdedicatedtoimprovingunderstanding ofthehostresponsetocanceranddevelopingnovelapproachestoimproveoutcomes.